Characterizing factors that may protect diabetic patients from the development of complications and prevent pancreatic p-cell failure has been difficult. We have been characterizing a large and unique cohort (n=400) of diabetic patients in the United States who are insulin-dependent for over 50 years (Medalist Study). The Medalists have mostly type 1 diabetes since mean age of diagnosis 11 6.3 years, duration of 56.6 5.7 years, HLA DR 3/4 prevalence 95%, and mean HbAlc of 7.3 1% at the time of study. Analyses showed that 42% of Medalists did not have significant retinopathy, nephropathy, or neuropathy. Surprisingly, no significant correlations were found between the presence of complications and HbA1 c, duration of disease and the presence of C-peptide. Excitingly, a combination of elevated and decreased levels of specific advanced glycation end-products (AGEs) appears to be associated with a decrease in the development of complications, suggesting the novel idea that some AGE indices may have value as "protective factors". Further, plasma C-peptide levels showed that 17% and 3% of Medalists still have levels greater than 0.3 or 0.5 ng/mL, respectively, and some are responsive to mixed meal tests. These findings suggest some Medalists have retained (3-cell function even after 50-80 years of T1 DM. Thus, the Medalist Study has identified a large cohort of T1 DM patients who may have factors that prevent the progression of complications and preserve p-cell function. We are proposing to: 1. Characterize the adverse or protective effects of AGE levels in a longitudinal study in the Medalists and their age-matched non-diabetic controls, 2. Evaluate retinal blood flow as a protective marker against progression of diabetic retinopathy in the Medalists, and 3. Evaluate the effects of plasma factors from Medalists with high and low levels of C-peptide on human islet cell function. PUBLIC HEALTH RELEVANCE: Identification of protective factors on the development of complications and the prevention of pancreatic beta cell failure has been difficult. We have characterized a unique cohort of diabetic patients in the United States who have been insulin dependent for over 50 years, called the Medalist Study. Findings from the Medalist Study have shown that a surprisingly high proportion of Medalists remain free from significant complications: proliferative diabetic retinopathy (49.4%), nephropathy (86.9%), neuropathy (39.4%), or cardiovascular disease (51.5%). In addition, 16% of the Medalists have positive C-peptide levels. Thus, we are proposing three studies to identify potential protective factors that can correlate to the absence of complications and the presence of islet beta cell function in this group of type 1 diabetic patients.